Inducible Regulatory T Cells (iTregs) in Non-Myeloablative Sibling Donor Peripheral Blood Stem Cell Transplantation

NCT01634217 | Completed Phase 1 DMC

• 2 other identifiers: 2012LS019MT2012-06R
• Study Type: interventional
• Target: 16
• Locations: 1 country
• Sites: 1

Brief Summary

This is a phase I single center dose escalation study with an extension at the best available dose to determine the tolerability of inducible regulatory T cells (iTregs) when given to adult patients undergoing non-myeloablative HLA-identical sibling donor peripheral blood stem cell (PBSC) transplantation for the treatment of a high risk malignancy. Up to 5 dose cohorts will be tested. Once the tolerable dose is determined for iTregs, enrollment will continue with an additional 10 patients using sirolimus/Mycophenolate mofetil (MMF) graft-versus-host disease (GVHD) prophylaxis to gain further safety information and to provide pilot data in this treatment setting.

Conditions

Acute Myelogenous Leukemia; Acute Lymphocytic Leukemia; Chronic Myelogenous Leukemia; Non-Hodgkin Lymphoma; Hodgkin Lymphoma; Chronic Lymphocytic Leukemia; Multiple Myeloma; Myelodysplastic Syndrome

Outcome Measures

Primary Outcomes (1)

• Incidence of grade 3-5 infusional toxicity

  Targeted adverse events and unexpected events not explained by the PBSCT or disease will be collected \[(1-4 hours after the iTreg infusion and before the PBSCT at day 0) and 24 hours and 48 hours after the iTreg infusion (+/- 2 hours)\]

  Within 48 Hours After iTregs Administration

Secondary Outcomes (5)

• Cumulative incidence of grade II-IV acute graft-versus-host disease (GVHD)

  Day 100

• Incidence of chronic graft-versus-host disease (GVHD)

  12 Months

• Relapse of Disease

  12 Months

• Survival

  1 Year

• Survival

  Day 100

Study Arms (5)

Cohort 1

EXPERIMENTAL

Administered 3 x 10\^6 iTregs/kg infusion

Biological: iTreg

Cohort 2

EXPERIMENTAL

Administered 3 x 10\^7 iTregs/kg infusion

Biological: iTreg

Cohort 3

EXPERIMENTAL

Administered 3 x 10\^8 iTregs/kg infusion

Biological: iTreg

Cohort 4

EXPERIMENTAL

Administered 10 x 10\^8 iTregs/kg infusion

Biological: iTreg

Cohort 5 Extension

EXPERIMENTAL

Administered 10 x 10\^8 iTregs/kg or best available dose using sirolimus/MMF as graft-versus-host disease (GVHD) prophylaxis. Immunosuppression will consist of a combination of sirolimus and mycophenolate mofetil (MMF). Sirolimus will be administered starting at day -3 with 8mg-12mg oral loading dose followed by single dose 4 mg/day. MMF will be administered starting on day -3 at a dose of 3 gram/day divided in 2 or 3 doses. Intravenous (IV) route between days -3 and +5, then may change to PO between days +6 and +30. Stop MMF at day +30 or 7 days after engraftment, whichever day is later, if no acute GVHD.

Biological: iTreg

Interventions

iTreg BIOLOGICAL

The iTregs will be infused at the assigned dose without a filter or pump slowly by gravity over 15-60 minutes. The iTregs should be given at least 4 hours before the peripheral blood stem cell (PBSC) infusion (MT2001-10).

Cohort 1; Cohort 2; Cohort 3; Cohort 4; Cohort 5 Extension

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• years of age with an HLA-identical sibling donor
• One of the following disease categories:
• Acute myelogenous leukemia - high risk CR1 (as evidenced by preceding MDS, intermediate to high risk cytogenetics, ≥ 2 cycles to obtain CR, erythroblastic or megakaryocytic leukemia; CR2+. All patients must be in CR as defined by hematological recovery (ANC \> 0.5x 109/L), AND \<5% blasts by light microscopy within the bone marrow with a cellularity of ≥15%.
• Acute lymphocytic leukemia - high risk CR1 \[t(9;22), t (1:19), t(4;11) or other MLL rearrangements\] or \>1cycle to obtain CR; CR2+. All patients must be in CR as defined by hematological recovery (ANC \> 0.5x 109/L), AND \<5% blasts by light microscopy within the bone marrow with a cellularity of ≥15%.
• Chronic myelogenous leukemia all types except blast crisis (note treated blast crisis in chronic phase is eligible)
• Non-Hodgkin lymphoma or Hodgkin lymphoma demonstrating chemosensitive disease
• Myelodysplastic syndrome with severe pancytopenia, leading to either transfusion dependency or increased risk for infections
• Performance status: Karnofsky ≥ 60%
• Adequate organ function within 28 days of study enrollment defined as:
• Liver: SGOT and SGPT \< 5.0 x ULN; total bilirubin \< 3 x ULN
• Renal: serum creatinine \< 2.0 mg/dl or glomerular filtration rate (GFR) \> 40 mL/min/1.73m2. Patients with a creatinine \> 1.2 mg/dl or a history of renal dysfunction must have glomerular filtration rate (GFR) \> 40 mL/min/1.73m2
• Albumin: \> 2.5 g/dL
• Cardiac: No decompensated CHF or uncontrolled arrhythmia; ejection fraction \> 35% within 6 weeks prior to study enrollment
• Pulmonary: No O2 requirements; DLCO \> 30% predicted within 6 weeks prior to study enrollment
• If recent mold infection (e.g. aspergillus) must have minimum of 30 days of therapy and responsive disease and be cleared by Infectious Disease

You may not qualify if:

• Pregnancy or breast feeding - women of childbearing potential must have a negative pregnancy test within 28 days of study enrollment.
• Prior myeloablative transplant within previous 3 months of study enrollment.
• Evidence of HIV infection or known HIV positive serology.
• Active serious infection.

Sponsors & Collaborators

• Masonic Cancer Center, University of Minnesota: lead

Study Sites (1)

Masonic Cancer Center, University of Minnesota

Minneapolis, Minnesota, 55455, United States

Location

Related Publications (1)

• MacMillan ML, Hippen KL, McKenna DH, Kadidlo D, Sumstad D, DeFor TE, Brunstein CG, Holtan SG, Miller JS, Warlick ED, Weisdorf DJ, Wagner JE, Blazar BR. First-in-human phase 1 trial of induced regulatory T cells for graft-versus-host disease prophylaxis in HLA-matched siblings. Blood Adv. 2021 Mar 9;5(5):1425-1436. doi: 10.1182/bloodadvances.2020003219.

  PMID: 33666654 DERIVED

MeSH Terms

Conditions

Leukemia, Myeloid, Acute; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Lymphoma, Non-Hodgkin; Hodgkin Disease; Leukemia, Lymphocytic, Chronic, B-Cell; Multiple Myeloma; Myelodysplastic Syndromes

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Leukemia, Lymphoid; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Myeloproliferative Disorders; Bone Marrow Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Lymphoma; Leukemia, B-Cell; Neoplasms, Plasma Cell; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hemorrhagic Disorders

Study Officials

• Margaret MacMillan, MD

  Masonic Cancer Center, University of Minnesota

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 2, 2012
• First Posted: July 6, 2012
• Study Start: November 8, 2013
• Primary Completion: December 1, 2017
• Study Completion: December 1, 2018
• Last Updated: January 18, 2019

Record last verified: 2019-01

Locations

US (1)